Abstract
The skeleton normally responds to mechanical environment to maintain the resulting elastic deformation (strain) of bone, while increased bone strength by an osteoporosis drug results in decreased bone strain. Thus, it can be hypothesized that the effect of osteoporosis therapy is limited by natural homeostatic system in the skeleton. This logic is consistent with the fact that there exists a powerful effect that returns bone mass to its pre-treatment level after the withdrawal of treatment with osteoporosis agents. The present hypothesis provides a new significant insight into the mechanisms by which osteoporosis drugs improve bone fragility. Here we briefly discuss the effects of teriparatide, romosozumab, and odanacatib on bones in animals and humans.
Similar content being viewed by others
References
Rizzoli R, Branco J, Brandi ML, Boonen S, Bruyere O, Cacoub P, Cooper C, Diez-Perez A, Duder J, Fielding RA, Harvey NC, Hiligsmann M, Kanis JA, Petermans J, Ringe JD, Tsouderos Y, Weinman J, Reginster JY (2014) Management of osteoporosis of the oldest old. Osteoporos Int. doi:10.1007/s00198-014-2755-9
Lindsay R, Miller P, Pohl G, Glass EV, Chen P, Krege JH (2009) Relationship between duration of teriparatide therapy and clinical outcomes in postmenopausal women with osteoporosis. Osteoporos Int 20:943–948
Matsumoto T, Takano T, Saito H, Takahashi F (2014) Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol. Bonekey Rep 3:513
Sakai S, Suzuki M, Tashiro Y, Tanaka K, Takeda S, Aizawa K, Hirata M, Yogo K, Endo K (2014) Vitamin D receptor signaling enhances locomotive ability in mice. J Bone Miner Res. doi:10.1002/jbmr.2317
Sugiyama T (2013) Vitamin D and calcium supplementation to prevent fractures in adults. Ann Intern Med 159:856
Sugiyama T, Tanaka S, Miyajima T, Kim YT, Oda H (2014) Vitamin D supplementation and fracture risk in adults: a new insight. Osteoporos Int. doi:10.1007/s00198-014-2798-y
Frost HM (2003) Bone’s mechanostat: a 2003 update. Anat Rec A: Discov Mol Cell Evol Biol 275:1081–1101
Sugiyama T (2013) Maternal vitamin D status during pregnancy and bone-mineral content in offspring. Lancet 382:767
Shanbhogue VV, Hansen S, Folkestad L, Brixen K, Beck-Nielsen SS (2014) Bone geometry, volumetric density, microarchitecture and estimated bone strength assessed by HR-pQCT in adult patients with hypophosphatemic rickets. J Bone Miner Res. doi:10.1002/jbmr.2310
Srinivasan S, Gross TS, Bain SD (2012) Bone mechanotransduction may require augmentation in order to strengthen the senescent skeleton. Ageing Res Rev 11:353–360
Milovanovic P, Zimmermann EA, Hahn M, Djonic D, Puschel K, Djuric M, Amling M, Busse B (2013) Osteocytic canalicular networks: morphological implications for altered mechanosensitivity. ACS Nano 7:7542–7551
Meakin LB, Galea GL, Sugiyama T, Lanyon LE, Price JS (2014) Age-related impairment of bones’ adaptive response to loading in mice is associated with sex-related deficiencies in osteoblasts but no change in osteocytes. J Bone Miner Res 29:1859–1871
Boonen S, Ferrari S, Miller PD, Eriksen EF, Sambrook PN, Compston J, Reid IR, Vanderschueren D, Cosman F (2012) Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective. J Bone Miner Res 27:963–974
Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L, San Martin J, Gallagher JC (2011) Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab 96:972–980
Sugiyama T, Meakin LB, Browne WJ, Galea GL, Price JS, Lanyon LE (2012) Bones’ adaptive response to mechanical loading is essentially linear between the low strains associated with disuse and the high strains associated with the lamellar/woven bone transition. J Bone Miner Res 27:1784–1793
Ellman R, Spatz J, Cloutier A, Palme R, Christiansen BA, Bouxsein ML (2013) Partial reductions in mechanical loading yield proportional changes in bone density, bone architecture, and muscle mass. J Bone Miner Res 28:875–885
Schulte FA, Ruffoni D, Lambers FM, Christen D, Webster DJ, Kuhn G, Muller R (2013) Local mechanical stimuli regulate bone formation and resorption in mice at the tissue level. PLoS One 8:e62172
Sugiyama T, Saxon LK, Zaman G, Moustafa A, Sunters A, Price JS, Lanyon LE (2008) Mechanical loading enhances the anabolic effects of intermittent parathyroid hormone (1–34) on trabecular and cortical bone in mice. Bone 43:238–248
Poole KE, Treece GM, Ridgway GR, Mayhew PM, Borggrefe J, Gee AH (2011) Targeted regeneration of bone in the osteoporotic human femur. PLoS One 6:e16190
Murad MH, Drake MT, Mullan RJ, Mauck KF, Stuart LM, Lane MA, Abu Elnour NO, Erwin PJ, Hazem A, Puhan MA, Li T, Montori VM (2012) Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network meta-analysis. J Clin Endocrinol Metab 97:1871–1880
Michalska D, Luchavova M, Zikan V, Raska I Jr, Kubena AA, Stepan JJ (2012) Effects of morning vs. evening teriparatide injection on bone mineral density and bone turnover markers in postmenopausal osteoporosis. Osteoporos Int 23:2885–2891
Luchavova M, Zikan V, Michalska D, Raska I Jr, Kubena AA, Stepan JJ (2011) The effect of timing of teriparatide treatment on the circadian rhythm of bone turnover in postmenopausal osteoporosis. Eur J Endocrinol 164:643–648
Sugiyama T, Taguchi T, Kawai S (2002) Adaptation of bone to mechanical loads. Lancet 359:1160
Sugiyama T, Meakin LB, Galea GL, Jackson BF, Lanyon LE, Ebetino FH, Russell RG, Price JS (2011) Risedronate does not reduce mechanical loading-related increases in cortical and trabecular bone mass in mice. Bone 49:133–139
Pierroz DD, Bonnet N, Baldock PA, Ominsky MS, Stolina M, Kostenuik PJ, Ferrari SL (2010) Are osteoclasts needed for the bone anabolic response to parathyroid hormone? A study of intermittent parathyroid hormone with denosumab or alendronate in knock-in mice expressing humanized RANKL. J Biol Chem 285:28164–28173
Ma YL, Zeng Q, Donley DW, Ste-Marie LG, Gallagher JC, Dalsky GP, Marcus R, Eriksen EF (2006) Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis. J Bone Miner Res 21:855–864
Cosman F, Eriksen EF, Recknor C, Miller PD, Guanabens N, Kasperk C, Papanastasiou P, Readie A, Rao H, Gasser JA, Bucci-Rechtweg C, Boonen S (2011) Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J Bone Miner Res 26:503–511
Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, Burnett-Bowie SA, Neer RM, Leder BZ (2013) Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 382:50–56
Brown JP, Reid IR, Wagman RB, Kendler D, Miller PD, Jensen JE, Bolognese MA, Daizadeh N, Valter I, Zerbini CA, Dempster DW (2014) Effects of up to 5 years of denosumab treatment on bone histology and histomorphometry: the FREEDOM study extension. J Bone Miner Res 29:2051–2056
Tsai JN, Uihlein AV, Burnett-Bowie SM, Neer RM, Zhu Y, Derrico N, Lee H, Bouxsein ML, Leder BZ (2014) Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT study. J Bone Miner Res. doi:10.1002/jbmr.2315
Robling AG, Turner CH (2009) Mechanical signaling for bone modeling and remodeling. Crit Rev Eukaryot Gene Expr 19:319–338
Moustafa A, Sugiyama T, Prasad J, Zaman G, Gross TS, Lanyon LE, Price JS (2012) Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporos Int 23:1225–1234
Ominsky MS, Niu QT, Li C, Li X, Ke HZ (2014) Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J Bone Miner Res 29:1424–1430
Padhi D, Jang G, Stouch B, Fang L, Posvar E (2011) Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res 26:19–26
McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster JY, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang YC, Libanati C, Bone HG (2014) Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 370:412–420
Morse A, McDonald M, Kelly N, Melville K, Schindeler A, Kramer I, Kneissel M, van der Meulen M, Little D (2014) Mechanical load increases in bone formation via a sclerostin-independent pathway. J Bone Miner Res. doi:10.1002/jbmr.2278
Delgado-Calle J, Riancho JA, Klein-Nulend J (2014) Nitric oxide is involved in the down-regulation of SOST expression induced by mechanical loading. Calcif Tissue Int 94:414–422
Jamal SA, Hamilton CJ, Eastell R, Cummings SR (2011) Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial. JAMA 305:800–807
Gardner JC, van Bezooijen RL, Mervis B, Hamdy NA, Lowik CW, Hamersma H, Beighton P, Papapoulos SE (2005) Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab 90:6392–6395
Sugiyama T, Taguchi T, Kawai S (2004) Spontaneous fractures and quality of life in cerebral palsy. Lancet 364:28
Spatz JM, Ellman R, Cloutier AM, Louis L, van Vliet M, Suva LJ, Dwyer D, Stolina M, Ke HZ, Bouxsein ML (2013) Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. J Bone Miner Res 28:865–874
Eisman JA, Bone HG, Hosking DJ, McClung MR, Reid IR, Rizzoli R, Resch H, Verbruggen N, Hustad CM, DaSilva C, Petrovic R, Santora AC, Ince BA, Lombardi A (2011) Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res 26:242–251
Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel DB, Scott BB, le Duong T (2012) Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res 27:524–537
Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, Samadfam R, Goetzmann JE, Scott BB, Kimmel DB, le Duong T (2012) Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res 27:509–523
Pennypacker BL, Chen CM, Zheng H, Shih MS, Belfast M, Samadfam R, le Duong T (2014) Inhibition of cathepsin K increases modeling-based bone formation, and improves cortical dimension and strength in adult ovariectomized monkeys. J Bone Miner Res 29:1847–1858
Fratzl-Zelman N, Valenta A, Roschger P, Nader A, Gelb BD, Fratzl P, Klaushofer K (2004) Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin Endocrinol Metab 89:1538–1547
Idris AI, Rojas J, Greig IR, Van’t Hof RJ, Ralston SH (2008) Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int 82:191–201
Ma YL, Zeng QQ, Chiang AY, Burr D, Li J, Dobnig H, Fahrleitner-Pammer A, Michalska D, Marin F, Pavo I, Stepan JJ (2014) Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment. Bone 59:139–147
Engelke K, Fuerst T, Dardzinski B, Kornak J, Ather S, Genant HK, de Papp A (2014) Odanacatib treatment affects trabecular and cortical bone in the femur of postmenopausal women—results of a 2-year placebo-controlled trial. J Bone Miner Res. doi:10.1002/jbmr.2292
Gajic-Veljanoski O, Tomlinson G, Srighanthan J, Adachi JD, Josse R, Brown JP, Cheung AM (2014) Effect of odanacatib on BMD and fractures: estimates from Bayesian univariate and bivariate meta-analysis. J Clin Endocrinol Metab. doi:10.1210/jc.2014-1162
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sugiyama, T., Kim, Y.T. & Oda, H. Osteoporosis therapy: a novel insight from natural homeostatic system in the skeleton. Osteoporos Int 26, 443–447 (2015). https://doi.org/10.1007/s00198-014-2923-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-014-2923-y